Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer

Abstract

Significance Most cancers are characterized by increased STAT3 activation where phosphorylated STAT3 levels are associated with reduced survival. The molecular mechanisms underlying aberrant STAT3 phosphorylation/activation in human malignancies have been elusive. Our findings provide a mechanistic basis for tumor-specific STAT3 hyperactivation in head and neck squamous cell carcinoma (HNSCC). We demonstrate that receptor-like protein tyrosine phosphatases, encoded by PTPR genes, including PTPRT , are commonly mutated in HNSCC where PTPR mutations are associated with increased phosphorylation of STAT3 in tumors. Several cancer-related PTPRT mutations localize to the substrate interaction surface of the enzyme catalytic domains. Expression of mutated PTPRT in HNSCC models markedly increases STAT3 activation, promoting cellular survival. PTPRT mutations may therefore serve as predictive biomarkers for STAT3 pathway inhibitors, suggesting new therapeutic opportunities.